We've developed extensive preliminary data showing that Sonic Hedgehog (Shh), produced by the hair follicles dorsal to the cortex, diffuses from the cells of origin to act within the brain to regulate the development of the hippocampal dentate gyrus and the migration of oligodendrocyte progenitors within the cortex at late embryonic and early postnatal stages. Using antibodies to extracellular Shh we are able to show that the amount of Shh reaching the developing cortex is reduced in mice with conditional ablation of Shh in the hair follicles and skin and that there is reduced signaling in transgenic signaling reporter mice in the brain. This indicates that the functional amounts of ligand reaching the cortex are reduced in these mice. These studies suggest the possibility that other protein ligands, if produced in the skin and hair follicles at high enough levels, would have access to the later embryonic and early postnatal developing brain, allowing us to circumvent some of the hurdles inherent in gene therapy or cell transplantation targeted to the cortex. In this proposal I will test this hypothesis and begin to lay the groundwork for determining the viability of this approach in humans. There are several difficult to treat disorders manifesting themselves around birth that may ultimately be amenable to this route of treatment. One particularly important syndrome is perinatal hypoxic-ischemic brain injury. Newborns with this syndrome have decreased oxygen supply due to events surrounding traumatic birth leading to significant injury including death of immature neurons and glial precursors. Recent studies have identified promising parenteral therapies in animals that are moving into human trials, but these face the possibility of causing increased off-target effects and morbidities because of the need to give these protein based agents intravenously. If they could be delivered locally and diffuse from the hair follicles and this might allow more targeted treatment with reduced morbidity. In addition, there are a host of genetic metabolic diseases that present with catastrophic consequences soon after birth due to enzyme deficiencies or other genetic lesions. Thus, I have developed this proposal to test the prospects for this approach.